BACKGROUND:
Alzheimer’s disease (AD) is a proteinopathy characterized by amyloid-β (Aβ) deposition and hyperphosphorylated tau aggregation, leading to amyloid plaques and neurofibrillary tangles. Dysregulation of the ubiquitin-proteasome system has been implicated in these processes. Ubiquitin C-terminal hydrolase L5 (UCHL5), a deubiquitinase that regulates proteasomal activity, plays a key role in the degradation of damaged proteins. However, its involvement in AD progression remains poorly understood. This study investigated associations between cerebrospinal fluid (CSF) UCHL5 levels and AD biomarkers across Aβ status and clinical diagnostic groups.
METHODS:
We compared CSF UCHL5 levels between 168 cognitively unimpaired (CU) and 540 cognitively impaired (CI) individuals (Table.1A), using ANCOVA adjusted for age and sex. To assess relationships with Aβ pathology, 460 individuals with CSF and PET measures were stratified into four Aβ status groups (190 A−A−, 12 A+A−, 44 A−A+, 214 A+A+; Table.1B), and ANCOVA was applied across them. The first “A” denotes tau ratio status and the second to Aβ-PET. Associations between UCHL5 and AD biomarkers (CSF Aβ42, p-tau181, hippocampal volume, AV45 and FDG) were assessed using generalized linear mixed models adjusted for age and sex. Voxel-wise analyses explored relationships with FDG- and Aβ-PET signals according to clinical diagnosis.
RESULTS:
CSF UCHL5 levels were higher in CU compared to CI individuals (Fig.1A). A−A− participants showed elevated UCHL5, with significant differences versus A+A+ and between A−A+ and A+A+ groups (Fig.1B). In CU and A−A− groups, UCHL5 was positively associated with p-tau181 (Figs.2A/H). Conversely, in CI and A+A+ individuals, UCHL5 correlated positively with CSF Aβ42 and hippocampal volume (Figs.2B/I/C/J). In CI individuals, UCHL5 was negatively associated with AV45 SUVRs reflecting Aβ burden in occipital, temporal, parietal, and frontal cortices (Figs.2D/E), while positive correlations were observed with FDG SUVRs, in prefrontal, temporal and parietal regions, as supported by voxel-wise FDG-PET analyses (Figs.2G/F).
CONCLUSION:
A consistent pattern in CSF UCHL5 levels was observed across amyloid-β status and clinical diagnosis, with higher levels in A−A− and cognitively unimpaired individuals. These findings suggest potential differences in UCHL5 across disease stages and Aβ profiles. Analyses are warranted to elucidate the underlying mechanisms and clarify the role of UCHL5 in AD pathology.